Introduction: Neoadjuvant therapy (NeoTx) is a key approach in managing gastrointestinal cancers,
aiming to reduce tumor size and enhance surgical outcomes. In addition to its direct
impact on tumors, NeoTx plays a significant role in shaping the tumor microenvironment
(TME), which is crucial for determining treatment outcomes. Alterations in lymphocytic,
myeloid, as well as stromal cell profiles within the TME, can change immune responses,
having impact on patients’ prognosis. This leads us to the hypothesis that NeoTx does
not only have a direct impact through cytotoxicity but also operates indirectly through
an immune cell-based manner. To address this, we employed a translational approach,
bridging preclinical findings and clinical patient outcomes to gain a more holistic
understanding of how NeoTx modulates the TME.
Methods: In our study, we investigated immune cell modulation in the TME using multiplex immunofluorescence
that enabled simultaneous detection of six markers in formalin-fixed, paraffin-embedded
(FFPE) tissue. For our investigation, we defined three panels: lymphocytic (CD3, CD4,
CD8, CD20, FOXP3, PanCK), myeloid (CD11b, CD33, CD68, CD206, HLA-DR, PanCK), and stromal
(CD11c, CD34, aSMA, NCAM, PRPH, PanCK). The cohort consisted of two groups: primary
resected with a TNM-, sex-, and age-matched cohort of NeoTx-treated patients (N=234).
For a more comprehensive understanding, we assessed pre-treatment biopsies of RCa-
and EAC-patients (N=50) within the same cohort. Quantitative and spatial analysis
was performed to assess shifts in immune cell populations and cell-cell interaction
after NeoTx.
Results: NeoTx led to a significant increase in CD8+T cells and tumor-infiltrating lymphocytes,
both associated with improved anti-tumor responses. A decrease in Tregs, known for
their immunosuppressive functions, was also observed, reducing local immune suppression.
In the myeloid compartment, NeoTx reduced the number of immunosuppressive M2-macrophages
and myeloid-derived suppressor cells (MDSCs), while promoting a shift toward pro-inflammatory
M1-macrophages.
Conclusion: NeoTx not only reduces tumor burden but also reshapes the immune cell profile, thereby
enhancing anti-tumor activity. These findings underscore the value of a translational
approach, to better predict treatment efficacy. This also supports the rationale for
combining NeoTx with immunotherapies to improve outcomes in rectal and esophageal
cancer.
